The University of Pittsburgh is uniquely suited, committed, and obligated to transform its academic culture, environment, and structure to further promote clinical and translational science as a distinct discipline locally and nationally. The University's Clinical and Translational Science Institute (CTSI) was founded in 2006 to lead an unprecedented inter-institutional initiative to achieve this goal. Over the past four years, CTSI revolutionized the University's research enterprise to develop, nurture, and support a new cadre of highly trained clinical and translational scientists and to enable their innovative research. Through novel institutional integration of pre-CTSA programs and the development of new interdisciplinary research and training initiatives, CTSI enabled our scientists to excel in generating new biomedical knowledge and translating this knowledge bidirectionally across the entire translational research spectrum. Our systematic approach to CTSI is based on an evolutionary transformation process that continuously evaluates programmatic outcomes, builds on past and current activities to create new and modify existing plans, and guides the evolution of CTSI's overarching goals. This dynamic approach resulted in the development of myriad infrastructure, programs, and services in ten CTSI Cores. It also serves as the basis for managing CTSI's next period of evolutionary growth. Over the next five years, we will: 1) transform our institution through an integrative collaborative approach to coalesce clinical and translational research and education programs, 2) transform our scientists through competency-based educational programs and the infusion of mentoring into all levels of training to advance the field of clinical and translational science through the next generation, 3) transform research by providing a robust resource environment to support team science and through the development of mechanisms for data sharing, and 4) transform health practice and the community through participatory partnerships that permit the full scope of bi-directional research translation. These transformations will lead to fundamental changes at the University of Pittsburgh that will enable CTSI faculty and investigators to conduct visionary, relevant clinical and translational research.